Pyrazole carboxylic acid hydrazides



United States Patent ()fiice 3,234,217 Fatented Feb. 8, 1966 The. present invention provides pyrazole-carboxylic acid-N-[-nitrofuryl-(2)-methylidene]-hydrazides, if desired their quaternary ammonium derivatives and salts thereof.

In the new compounds the carboxylic acid hydrazide group is pretcrably in one of the positions 3, 4 or 5 of the pyrazole nucleus, above all in position 4. The new compounds can be substituted in any desired manner. More especially, the pyrazole nucleus may contain further su'ostituents; above all it may be N-substituted, for example by unsubstituted or substituted hydrocarbon radicals, saturated or unsaturated heterocyclic or hcterocyclicaliphatic radicals.

Hydrocarbon radicals are, for example, saturated or unsaturated aliphatic, alicyclic, alicyclic-aliphatic, araliphatic or aromatic hydrocarbon radicals, such as lower straight or branched alkyl or alkenyl radicals, for example, methyl, ethyl, propyl, isopropyl, straight or branched radicals linked in any desired position, being butyl, pentyl, hexyl or heptyl, allyl or methallyl radicals, cycloalkyl or cycloalkenyl radicals such as cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl radicals, cycloalkylor alkenyl-alkyl radicals, such as cyclopentylor cyclohexenyl-methyl, -ethyl or -propyl radicals, aralkylor aralkenylsuch as phenyl-methyl, -ethyl, vinyl or -propyl radicals or aryl radicals, more especially phenyl radicals. Suitable heterocyclic or heterocyclic-aliphatic radicals are above all mono-nuclear ones, such as pyridyl radicals.

As substituents of the aforementioned aliphatic radicals there may be mentioned more especially free or substituted hydroxyl, mercapto or amino groups in which the substituents are preferably of aliphatic nature, for example lower alkoxy, allaylmercapto or monoor di-alkylor -cyclo-alkyl-amino groups, alkylene-arnino, oxaalkyleneamino, aza alkyleneamino or thiaalkylene amino groups, such as methyl'-, ethyl-, propyl-, butyl-, pentylor hexyl-oxy or -mercapto groups, methyl-, dimethyl-, ethyl-, diethyl-, propyl-, dipropyl-, N-methyl-N-propyl-, N-methyl-N-cyclopropyl, butyl-, dibutyl-amino groups, pyrrolidino, piperidino, morpholino or piperazino groups, for example the piperazino, N-methylpiperazino or N- hydroxyethyl-piperazino groups.

The aliphatic radicals may also be substituted by halogen atoms such as chlorine, bromine or iodine.

The alicyclic radicals may contain above all lower alkyl radicals.

Aromatic or heterocyclic radicals may contain above all halogen atoms or the abovementioned free or substituted hydroxyl, mercapto or amino groups, 'alkyldioxy, .alkylenedioxy, nitro groups or free or converted carboxyl groups. In the alicyclic-aliphatic, araliphatic and heterocyclic-aliphatic radicals both components may be substituted as described above.

Substituents at the ring C atoms of the pyrazole ring are more especially amino groups, such as the amino group or an acylamino group, e.g., a lower alkanoyl, benzoyl or phenylalkanoyl group or a lower alkyl or phenyl radical, such as methyl, ethyl, propyl or phenyl; the phenyl radicals may be substituted as indicated above.

Furthermore, the new compounds may also be substituted for example at the hydrazide nitrogen, above all by one of the aforementioned substituted or unsubstituted hydrocarbon or heterocyclic groups, more especially by alkyl.

Quaternary ammonium derivatives are above all the alkyl or benzyl ammonium compounds of tertiary bases. From among pyrazole-carboxylic acids from which the new compounds may be derived there may be mentioned especially: Pyrazole-carboxylic acids of the formula X ufl-O 0 OH X,-'-[o 0 OH L ac. or X:

in which X and X each represent hydrogen, alkyl, oxyalkyl, halogenalkyl, tertiary aminoalkyl or phenyl radicals, and X and X each represent a hydrogen atomor an amino, alkyl or phenyl group.

The new compounds develop a valuable antibacterial action, above all on cocci. They further act against protozoae, such, for example as trypanosomes, trichromo nades or amoebae. They can therefore be used as chemotherapeuticals, for example in treating streptococcal, staphylococcal or protozoan infections in animals or humans. They are also active against colibacteria and can be used as urine-disinfectants. They can also be used as intermediates for the manufacture of me'dlcaments.

Especially valuable are those pyrazole compounds of the kind defined above in which the pyrazole nucleus is N-unsubstituted or N-substituted by one of the specified radicals and contains in addition to the carboxylic acid hydrazide group, a free or substituted amino group attached to a carbon atom; of special value are the com pounds of the formulae their N-acyl derivatives and salts thereof. In these formulae R represents an alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, halogenoalkyl or tertiary aminoalkyl group in which the alkylene chains contain 2 to 4 carbon atoms, or it may represent a phenyl, benzyl or pyridyl radical, and R represents a hydrogen atom or a lower alkyl radical. The tertiary amino group is above all a di-lower alkylamino, alkyleneamino, oxaalkyleneamino or azaalkylene amino group, more especially a dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, piperazino or N-alkyl-piperazino group. The phenyl or benzyl radicals may contain lower valkoxy, alkyl-mercapto, alkyl-, alkylenedioxy groups and/ or halogen atoms.

The acyl radicals are more especially those of lower fatty acids or benzoic acids.

The invention provides above all the compounds of the formula r 3 t and their salts, in which N B represents a lower dialkylamino, morpholino, piperazino, pyrrolidino or piperid-ino group; n=2 or 3; and R represents hydrogen or methyl above all the 2-(,B-diethylaminoethyl)-3-amino-4-carb0xylic "acid-N-(-nitro 2 furfuryliden:e)-hydrazide of the formula and salts thereof, and Z-(B-dimethylamino-ethyl)-3- amino-pyrazole-4-carboxylic acid-N'-(5-nitro-2-furfurylidene)-hydrazide and its salts.

The new compounds are prepared by methods known per se. Advantageously, a pyrazole-carboxylic acid hydrazide is condensed with a 5 nitrofuran-(2)-carbonyl compound, more especially with S-nitrofuran-Z-aldehyde, to form the hydrazone. This condensation is carried out in the usual manner, and the carbonyl group may also be in a reactively converted form. Thus it is possible to use, for example, acetals, thioacetals, oximes, bisulfite compounds or acylates of the carbonyl compounds.

The aforementioned reactions are carried out in the usual manner, preferably in the presence of diluents, condensing agents or catalysts, at room temperature or below or above it, if desired, under superatmospheric pressure.

The starting materials are known or can be made by methods known per se. If desired, they may be used in the form of their salts or quaternary compounds.

The starting materials used, namely the 3-hydroxyor 3-aminopyrazole-4-carboxylic acid hydrazides which are substituted in position 1 or 2 by alkyl, hydroxyalkyl, aminoalkyl preferably secondary or tertiary aminoalkyl or a chlorophenyl radical, as well as their salts, are new and form another object of the present invention. They are obtained in the usual manner, for example, by reacting a suitable carboxylic acid or a reactive derivative thereof with hydrazine.

Depending on the reaction conditions and starting materials used the new compounds are obtained in the free form or in the form of salts thereof. The salts of the new compounds can be converted in the known manner into the free compounds, acid addition salts, for example by reaction with a basic agent, or a metal salt if desired by reaction with an acid. On the other hand, a resulting acid compound can be converted into a salt by treat ment with a basic agent, for example with a hydroxide or carbonate of an alkali metal such as sodium hydroxide or potassium carbonate; or a resulting free base on the other hand can be made into a salt with an inorganic or organic acid. Acid addition salts are advantageously prepared with therapeutically useful acids, for example hydrohalic acids, for example hydrochloric or hydrobromic acid, perchloric acid, nitric or thiocyanic acid, sulfuric or phosphoric acids, or organic acids, such as formic, acetic, propionic, glycollic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4- aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, para-toluenesulfonic, naphthalenesulfonic or sulfanilic acid, or methionine, tryptophan, lysine or arginine. The salts may be mono-salts or poly-salts.

When a resulting compound contains a tertiary amino group it can be converted by a known method into a quaternary ammonium compound, more especially by reaction with an alkylor benzylhalide, -sulfate or -sul fonate such, for example, as methyl-, ethyl-, or propyl- 4" chloride, -bromide or -iodide, or with a dialkyl sulfate, for example dimethyl sulfate or diethyl sulfate. Quaternary ammonium salts can also be converted into ammonium hydroxides, for example by the action of freshly pre cipitated silver oxide on an ammonium halide, or by the action of barium hydroxide solution on an ammonium sulfate; from these ammonium salts other ammonium salts can be prepared by reaction with acids, for example with those mentioned above.

The new compounds are intended to be used as medicaments in the form of pharmaceutical preparations containing them in admixture with an organic or inorganic solid or liquid pharmaceutical vehicle suitable for local, enteral (for example, oral) or parenteral administration. Suitable vehicles are substances that do not react with the new compounds, such for example as water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils,

k benzyl alcohols, gums, polyalkylene glycols, White pe- Example 1 A solution of 14.1 grams of 3-aminopyrazole-4-carboxylic acid hydrazide and 15 grams of 5-nitrofuran-2-aldehyde in 300 cc. of ethanol is heated for 3 hours at the boil, allowed to cool and the precipitate is suctioned oh and recrystallized from dimethyl formamide, to yield 3-aminopyrazole-4-carboxylic acid-N'-(5-nitro-2-furfuryl-idene)- hydrazide of the formula in yellow crystals melting at 240 C. with decomposition. 3-aminopyrazole-4-carboxylic acid hydrazide used as starting material is prepared in the following manner:

A mixture of 15.5 grams of 3-amino-4-carbethoxypyrazole and 20 grams of hydrazine hydrate is heated for 5 hours on a bath at 120 C., then allowed to cool and the residue is crystallized from much boiling ethanol, to yield 3-aminopyrazole-4-carboxylic acid hydrazide of the formula in colorless crystals melting at 221-222" C.

Example 2 A solution of 13.9 grams of 2-(/3-diethylaminoethyl)-. 3-aminopyrazole-4-carboxylic acid hydrazide hydrochlo ride in 250 cc. of aqueous ethanol of 90% strength is treated with a solution of 7.05 grams of 5-nitrofuran-2- aldehyde in cc. of absolute ethanol and the whole is refluxed for 35 minutes, then allowed to cool, and the crystals are suctioned off. The resulting product is the 2 (5 diethylaminoethyl)-3-aminopyraz0le=4-carboxylic aq r (itFQ ur r idsml-h s s h dr hl 'ds of he. enne HTTTEOOrNH-NECHT (3211:, e tin a 5 C- wi h. d ompos ion,

Z-(gl-fdiethylgrrnittfithrl)? mi nopyragolei :carboitylic. acid hydragide hydrochlor usedf'asstarting material is prepared in the' following rnannerz l A mixture of 25.4 grams of 2-(,B-diethylarninoethyl)- 3-arnino-4-carbethoxypyrazole and 75 cc. of hydrazine hydrate is heated for 6 hours at 130 C-., then cooled, and the crystals are suctioned off and recrystallized from ethanol, to yield Z-(B-diethylaminothyl)g3 aminopyrazole-4-carboxylic acid hydrazide of the forniula 0 ;NHi

(EHgCHgN 2 melting at: 143 145 6.

A solution of 11.7 grams oi -this base in cc. oi ah; solute ethanol is treated. with 3 4.4 cc. of; 1.42 1\ 1-et;hanoliov hydrochloric acid, whereupon the hydrochloride Of 2-( 3; diethylaminoethyl) ami QPY T ZQIrf CaJ 9XY a id. hydrazide melting at ESQ-1 521 C. separates out.

Example 3 A solution of 8.7 grams of 2-(j8piperidinoethyl)-3- aminopyrazole-4-carboxy1ic acid hydrazide hydrochloride in 600 cc. of aqueous ethanol of 90% strength is treated with a solution of 4.23 grams ofS-nitrofurah-Z-aldehyld in cc. of ethanol and the mixture is refluxed for 35 mi ute t e While being al w web at! the crystals are suctione doil. to yield 2-(fi-piperidinoethyl) raminqpy z lsA-ca bo yli a l -N'-(firnitr uiurturyl- QU Qr Y Zi hy ro hlor de 9 the iQ mu a,

melting at 250 C. with decomposition.

2 (B p p n l yll 3-amin9shawls-H rbWK? cid.- by razid hydrochlor de u e as. star i mat ia is Prepared the followin manne A mixture of 53.2 grams of 2-(ti-piperidinoethyQ-Q: m nqr -sarb th ypyr ol and r ins of hyd s y r te is hea ed or 6 ou s. o a b th t 9; a owed t c ol, nd t e Cr tals e s sti n Q and ry ta lized f om e hano t ie d. .:(o2 w mthyl)e-amincAwa bpryHs acid. h d z ds t he is mula melting at 183-184" C.

A solution of 16 grams of;-tl 1e above base, in 150 cc. of warm ethanol is treated with 44.8, cc, of 1.42 Isl-ethanolic hydrochloric acid. The separating crystals are suctioned to yield the hydroshlsr de 9i. l-(fi ii rid aq- 6. ethyl),-3-aminopyrazole-4-carboxylie acid hydrazide melt.- ing at 237-239 C. A v U i '7 7 Example 4 A hot solution of 8.7 grains of Z-(fianorpholinoethyh- 3-arninopyrazole-4-carboxylic acid hydrazide hydrochloride in 600 cc. of aqueous ethanol of strength is mixed with a solution of 4.23 grams of 5-nitrofuran-2- ldehy e in ,9. eth no nd t mix ur s. refl xed for 35 minutes, then allowed to cool, and the. p r e cipa e yst ls a e s i t c rd o t. o, ield -lfi-mst fis n t y 3.: m sp tzql r i ic ai l N'- (5 trdur rr i suskhr az d h d t shlq isi f t e drm a melting at 193196 C.

The 2-substituted 3-arninopyrazoles used in the present xam l nd n e pre e i e a es a start n mate: rials are obtained in the follov'ving manner:

(a) A sol f 5: ram o -tfi-hydr xy mwhethromi m M1 c t n l ch o i sn eva orat n v es and. t r idue. s were ce w t and adjuste with -sed um hyd xi s lu ion o. pH T e. rec a e s he si fs qils 1 nd rel crystallized from ethanol, to yield 2- (,8- chloroethyl)-3- amino-4-cyanopyrazole in yellow crystals melting at154- melting at 103- 109" C.

A mixture of 103 gra ns of 2-(,8-diethylaminoethyl)-3- arnino-4-cyanopyrazole and 80 cc. of concentrated sulfuric acid in 1.6 liters of absolute ethanol is heated in an autoclave for 3 hours at C, allowed to cool, evaporated in vacuo, and the residue is poured into a cooled sodium bicarbonate sqlutiog and repeatedly extracted with ether. The ethereal solution is dried and evaporated. Fractional distillation of the residue yields 2-( .-die t hylm ro thyll:35o ies qar i hq yai se l he re.

mula

CHiCHzN" which boils at 139141 C. under a pressure of 0.05 mm. Hg.

(b) A mixture of 170 grams of 2-(fl-chloi'oethyD-3- amino-4-cyanopyrazole and 8 00 cc. of piperidine is heated for 1 /2 hours on a Water bath, evaporated in vacuo, and the residue is triturated with water. Theinsoluhle cons'tituent so obtained is 2-(,B-piperidinoethyl)-'3-amino-4- cyanopyrazole of the formula l I \N/ HgCHr-N which melts at 1375-1385 C. after having been recrystallized from alcohol.

A mixture of 65.7 grams of 2-(fi-piperidinoethyl)-3 amino-4-cyanopyrazole and 81 grams of concentrated sulfuric acid in 1.2 liters of absolute alcohol is heated in an autoclave for 3 hours at 140 C., allowed to cool and evaporated in vacuo. The residue is poured into a cooled sodium bicarbonate solution and repeatedly extracted with ether. The ethereal solution is dried and evaporated, to yield Z-(B-piperidinoethyl)-3-amino-4-carbethoxypyrazole of the formula MKS o 0 02115 \N/ NH:

which melts at 86-87 C. after recrystallization from pctroleum ether. v

. (c) A mixture of 136 grams of 2-'(fi-chloroethyl)-3- amino-4-cyanopyrazole and 480 cc. of morpholino is heated for 1 /2 hours on a boiling water bath, evaporated in vacuo and the residue is triturated with water. The insoluble constituent is recrystallized from ethanol, to yield 2 (,B-morpholinoethyl)-3-amino-4-cyanopyrazole of the formula J N/ :NHZ

C 2H 0H N b melting at 123-124 C.

98 grams of 2-(5-morpholinoethyl)-3-amino-4-cyanopyrazole and 71 cc. of concentrated sulfuric acid in 1.55 liters of absolute ethanol are heated in an autoclave for 3 hours at 140 C., allowed to cool, evaporated in vacuum and the residue is poured into a cooled sodium bicarbonate solution and repeatedly extracted with ether. The ethereal solution is evaporated and the residue recrystallized from ether-petroleum ether, to yield 2-.(B-morpholinoethyl)-3-amino-4-carbethoxypyrazole of the formula HgCHzN O melting at 60-63 C. p

"The hydrochloride of this compound, melting at 232-234" C., is obtained by dissolving it in ethanol and treating the solution with ethanolic hydrochloric acid.

A mixture of 53.6 grams of 2-( 8-morpholinoethyl)-3- amino-4-carbethoxypyrazole and 150 grams of hydrazine hydrate is heated for 6 hours on a boiling water bath, allowed to cool and the precipitated crystals are suctioned ofi and recrystallized from ethanol, to yield Z-(B- morpholinoethyl)-3-aminopyrazole-4-carboxylic acid hydrazide of the formula GO NHN Hn emomN' 0 melting at 193 194" 0;

8 A solution of 10.16 grams of this base in 220 cc. of ethanol is treated with 28.2 cc. of 1.42 N-ethanolic hy drochloric acid, whereupon the hydrochloride of 2-(,8- morpholino-ethyl)-3-aminopyrazole-4-carboxylic acid hydrazide, melting at 228230 C., precipitates.

Example 5 A solution of 9.1 grams of 2-isopropyl-3-aminopyrazole-4-carboxylic acid hydrazide and 7.5 grams of S-nitrofuran-Z-aldehyde in 150 cc.- of ethanol is heated for 3 hours at the boil, then allowed to cool and the precipitate is suctioned oifand recrystallized from much ethanol, to yield 2-isopropyl-3-aminopyrazole-4-carboxylic acid-N'- (5-nitro-2-furfurylidene)-hydrazide of the formula A solution of 7.3 grams of 1-isopropyl-3-aminopyrazole-4-carboxylic acid hydrazide and 5.7 grams of 5- nitrofuran-Z-aldehyde in 200 cc. of ethanol is heated for one hour at the boil, then allowed to cool, the precipitate is suctioned off and recrystallized from much ethanol, to yield 1-isopropyl-3-aminopyrazole-4-carboxylic acid- N'-(5-nitro-2-furfurylidene)-hydrazide of the formula in yellow crystals melting at 247-249 C.

manner:

A mixture of 39.4 grams of l-isopr'opyl-3-amino-4- carbethoxypyrazole and 40 cc. of hydrazine hydrate is heated for 6 hours ona bath at 120 C.,- then allowed to cool and the residue is crystallized from much boiling ethanol, to yield 1-isopropyl-3-aminopyrazole-4-carb0x-' ylic acid hydrazide of the formula 0 O-NH-NH,

in colorless crystals melting at 146-148 C.

Example 7 A mixture of 15 grams of 2-(fi-diethylaminoethyD-3- hydroxy-4-carbethoxypyrazole and 75 cc. of anhydrous hydrazine is heated for 5 hours at 110 C. The reaction mixture is then evaporated in a water-jetvacuum at C.

1-isopropyl-3-aminopyrazole-4-carboxylic acid hydra-' zide used as starting material is prepared in the following and the residue is dissolved in 50 cc. of water. The reaction solution -is adjusted with concentrated hydrochloric acid to pH 1. The acid solution is treated with grams of S-nitrofuran-Z-aldehyde in 40 cc. of alcohol, whereupon a voluminous yellow precipitate settles out which is suctioned off and boiled with 400 cc. of methanol of 90% strength. The insoluble constituents are filtered OE and the filtrate is allowed to cool, to yield the hydrate of 2 (e diethylaminoethyl) 3 hydroxypyrazole 4- carboxylic acid-N'-(5-nitro2-furfurylidene)-hydrazide hydrochloride of the formula in yellow crystals melting at 159-162 C.

Z-(fi-diethylaminoethyl) 3-hydroxy-4carbethoxypyrazole used as starting material is prepared in the following manner:

50 grams of ethoxymethylene ethyl malonate and 40 grams of fi-diethylaminoethylhydrazine in 75 cc. of ethanol are heated for 5 hours at the boil. The reaction prod not is evaporated in vacuo and the residue is recrystallized from methylene chloride-l-diethyl ether, to yield 2- (fi-diethylaminoethyl) 3-hydroxy-4-carbethoxypyrazole of the formula in crystals melting at 155 C.

Example 8 A solution of 5 grams of 2-(para-chlorophenyl)-3 aminopyrazolei-carhoxylic acid hydrazide in 100 cc. of boiling ethanol is treated with 3 grams of S-nitrofuran-Z- aldehyde in cc. of ethanol and the mixture is heated for minutes at the boil. The precipitate is filtered off and recrystallized from dimethyl formamide-l-methanol, to yield 2-(para-chlorophenyl)-3-aminopyrazole-4-carboxylic acid-N'-(S-nitro-Z-furfurylidene)-hydrazine of the formula in yellow crystals melting at 257 C.

2- (para-chlorophenyl)-3 aminopyrazole- 4 -c arhoxylic acid hydrazide used as starting material is prepared in the following manner:

A mixture of 30 grams of 2- (para-chlorophenyU-3- amino-4-carbethoxypyrazole and 150 :cc. of hyrazine hydrate is heated for 7 hours at 120 C., then cooled and the precipitate formed is recrystallized from dimethyl formamide-E-ethanol, to yield 2-(para-ch1orophenyl)-3-arninopyrazole-4carboxylic acid hydrazide of the formula in white crystals melting at 236 C.

Example 9 A solution of 9.1 grams of 2-(B-hexamethy1eneiminoethyl)-3-aminopyrazole-4-carboxylic acid hydrazide hydrochloride in 350 cc. of ethanol of strength is treated with 4.23 grams of S-nitrofuran-Z-aldehyde in 60 cc. of ethanol and the mixture is refluxed for 35 minutes, then allowed to cool, and the precipitated crystals are suctioned ofi, to yield 2-(B-hexarnethyleneiminoethyl)-3- aminopyrazole 4 carboxylic acid-N 5 nitrofurfurylide e)-hydrazide hydrochloride of the formula melting at IDS-106 C.

A mixture of 116.5 grams of Z-(fi-hexamethyleneiminoethyl)-3-amino-4-cyanopyrazole and 80 cc. of concentrated sulfuric acid in 1.75 liters of absolute ethanol is heated in an autoclave for 3 hours at C., then allowed to cool and the reasidue is mixed with 200 grams of water and 250 grams of sodium bicarbonate and ex tracted with ether. The ethereal solution is evaporated and yields crude 2-(fl-hexamethyleneiminoethyl)-3-amino-4-carboethoxypyrazole of the formula CHg-CHCH2 HZCHflN CHg-CH:CH2 A solution of 16.4 grams of this base in 10 cc. of ethanol is treated with 36.4 cc. of 1.61 N-ethanolic hydrochloric acid. The solution is considerably concentrated and then mixed with diethyl ether, whereupon the hydrochloride melting at *l72-l-74" C. separates out.

A mixture of 67 grams of crude Z-(fl-hexamethyleneiminoethyl)-3-amino-4-carbethoxypyrazole and cc. of

11 hydrazine hydrate is heated for 8 /2 hours at 130 C., then allowed to cool, and the crystals are suctioned off and recrystallized from ethanol, to yield Z-(B-hexamethyleneiminoethyl)-3-aminopyraz-ole-4-carboxylic acid hydrazide of the formula CHrCHz-CHQ melting at l66167 C.

When a solution of 35 grams of this base in 250 cc. of ethanol is treated with 82 cc. of 1.61 N-ethanolic hydrochloric acid, the hydrochloride melting at 1861'88 C. precipitates.

Example A solution of 13.12 grams of 2- (fi-isopropylaminoethyn- 3-aminopyrazole-4-carboxylic acid hydrazide hydrochloride in 300 cc. of ethanol of 90% strength is treated with -7;05 grams of 5-nitrofuran-2-aldehyde in 40cc. of absolute ethanol and the mixture is refluxed for 35 minutes, then cooled, and the crystals are suctioned off, to yield 2-(5- isopropylaminoethyl)-3-aminopyrazole-4-carboxylic acid- N'-(S-nitrofurfurylidene)hydrazide hydrochloride of the formula NH: CH3

on onmuoir XLFLCN NH N 2 CH3 -HCl which is treated with 250 cc. of absolute ethanol, freed by filtration from a little insoluble material and the filtrate is treated with ethanolic hydrochloric acid to establish a pH of 4. 2- (,B-isopropylaminoethyl)-3-amino-4-cyanopyrazole hydrochloride melting at 275276 C, crystallizes spontaneously from the solution.

58 grams of crude 2-(fi-isopropylaminoethyl)-3-arnino- 4-cyanopyrazole and 80 cc. of concentrated sulfuric acid in 1.8 liters of absolute ethanol are heated in an autoclave for 3 hours at 140 C., allowed to cool, evaporated in vacuo, and the residue is treated with 250 cc. of Water and 250 grams of sodium bicarbonate and extracted with chloroform. The chloroform solution is evaporated and yields crude 2,- (/3 isopropylaminoethyl)-3-amino-4-carbethoxypyrazole which is heated with 1 65 cc. of hydrazine hydrate for 6 hours at 130 C., then allowed to cool, and the crystals are suctioned off and dissolved in ethanol. The solution is adjusted with ethanolic hydrochloric acid to pH=6, and the precipitated crystals are suctioned oil and recrystallized twice from ethanol of 95% strength,

to yield 2( 3-isopropylaminoethyl)-3-arninopyrazole-4- carboxylic acid hydrazide hydrochloride of the formula NH: I /0 H3 C H; C HZNH CH melting at l74l-77 C.

Example 11 melting at 235 C. with decomposition.

2 (B methylaminoethyl) 3 aminopyrazolel-carboxyl-ic acid hydrazide hydrochloride used as starting material is prepared in the following manner.

A mixture of grams of Z-(B-chloroethyl)-3-amino-4- cyanopyrazole and 250 cc. of methylamine is heated for 1 /2 hours at C. in a closed vessel, then evaporated to dryness, and the residue is heated in an autoclave with 80 cc. of concentrated sulfuric acid and 1.6 liters of absolute ethanol for 3 hours at C., allowed to cool, evaporated in vacuo and the residue is treated with 250 cc. of Water and 250 grams of sodium bicarbonate and repeatedly extracted with ether. Evaporation of the ethereal solution yields crude 2-(l8-methylaminoethyl)-3- amino-4-carbethoxypyrazole of the formula W-C O O C2115 Its hydrochloride melting at l63l66 C. is prepared by dissolving it in ethanol and adding ethanolic hydrochloric acid.

A mixture of 53 grams of the crude Z-(fl-methylaminoethyl) 3-arnino-4-carbethoxypyrazole prepared as described above and cc. of hydrazine hydrate is heated for 6 hours at 130 C. then allowed to cool, and the precipitated crystals are suctioned oif and washed with ethan01, to yield crude 2 (B methylaminoethyl)-3-aminopyrazole-4-carboxylic acid hydrazide of the formula W-C ONHNH:

A suspension of 30.8 grams .of this hydrazide in 600 cc. of ethanol and 100 cc. of water is treated with 72.3 C0. of 2.15 N-ethanolic hydrochloric acid, then evaporated in vacuo, the residue is triturated with a small amount of ethanol and the crystals are suctioned off, to yield -2 (3- methylaminoethyl)-3-arninopyrazole-4-carboxylicacid hydrazide hydrochloride melting at 212 215C.

hydrazide hydrochloride of the formula -HCl melting at 279 C. with decomposition.

2 (/8 dimethylarninoethyl) 3-aminopyrazole-4-carboxylic acid hydrazide hydrochloride used as starting material is prepared in the following manner:

A mixture of 68 grams of 2 (B-chloroethyl)-3-arnino- 4-cyanopyrazole and 200' cc. of'dimethylamine is heated for 1 /2 hours at 100 C. in a closed vessel, then evaporated in vacuo, the residue is triturated with 2 N-sodium hydroxide solution, and the crystals are suctioned off and Washed with water, to yield Z-(fi-dimethylaminoethyl)-3-amino-4-cyanopyrazole of the formula melting at 121-l23 C. Recrystallization from ethyl acetate-i-petroleum ether raises the melting point to 125- 126 C.

A mixture of 95 grams of 2 (,S-dimethylaminoethyD- 3-amino-4-cyanopyrazole and 80 cc. of concentrated sulfuric acid in 1.6 liters of absolute ethanol is heated in an autoclave for 3 hours at 140 C., allowed to cool, then evaporated in vacuo and the residue is treated with 250 cc. of water and 250 grams of sodium bicarbonate and extracted with ether. Evaporation of the ethereal solution yields crude 2 (ti-dimethylaminoethyl)-3-arnino-4- carbethoxypyrazole which is mixed with 210 cc. of hydrazine hydrate and heated for 6 hours at 130 C., then allowed to cool, and the crystals are suctioned oh and washed with ethanol, dissolved in 2.5 liters of absolute ethanol and the solution is treated with 243 cc. of 0.95 N- ethanolic hydrochloric acid. The solution is concentrated to about 1.5 liters, whereupon 2 (,8 dirnethylaminoethyl)-3-arninopyrazole-4-carboxylic acid hydrazide hydrochloride of the formula I CHa 'HCl melting at 198200 C. separates out.

Example 13 A solution of 10.5 grams of 2 (,B-n-propylaminoethyl) 3-aminopyrazole-4-carboxylic acid hydrazide hydrochloride in 400 cc. of ethanol of 90% strength is 14 mixed with 5.65 grams of S-nitrofuran-Z-aldehyde in 40 cc. of absolute ethanol and refluxed for 35 minutes, then allowed to cool and the crystals are suctioned off, to yield 2. (fl-n-propylarninoethyl)-3-arninopyrazole-4-carboxylic acid N'-(5-nitro-2-furfurylideneJ-hydrazide hydrochloride of the formula l l... N [Nm L I dmonzNuomoHzcHa melting at 232 C.

2-(fl-n-propylaminoethyl)-3-aminopyrazole 4 carb oxylic acid hydrazide hydrochloride used as starting material is prepared in the following manner:

A mixture of grams of Z-(fi-chloroethyl)-3-amino-4- cyanopyrazole and 330 cc. of n-propylamino is heated for 1 hours at C. in a closed vessel, then evaporated in vacuo and the residue is triturated with Water. The insoluble constituent is crude 2-(fi-n-propylaminoethyn- 3-amino-4cyanopyrazole of the formula which is boiled in absolute ethanol, =ireed from a small amount of nndissolved material and treated with alcoholic hydrochloric acid to establish a pH of 3.5, whereupon the hydrochloride of 2-(B-n-propylarninoethyl)-3-amino- 4-cyanopyrazole melting at 267-268 C. separate-s out.

A mixture of 73 grams of crude Z-(B-n-propylaminoethyl)-3-amino4-cyanopyrazole and 60 cc. of concentrated sulfuric acid in 1.35 liters of absolute ethanol is heated in an autoclave for 3 hours at C, then allowed to cool and evaporated in vacuo. The residue is treated with 200 cc. of water and. grams of sodium bicarbonate and extracted With chloroform. On evaporation, the chloroform solution yields crude Z-(fi-n-propylaminoethyD-3-amino-4-carbethoxypyrazole of the for- This crude product is dissolved in absolute ethanol, the solution is adjusted to pH 3 with ethanolic hydrochloric acid and evaporated in vacuo. The residue is dissolved in Water, a little insoluble material is filtered off and the clear solution is again evaporated. The residue is recrystallized from ethanol-i-cliethyl ether and yields the hydrochloride of 2-(B-n-propylarninoethyl)-3 amino 4- carbethoxypyrazole melting at 148-151 C.

A mixture of 72 grams of crude Z-(B-n-propylaminoethyl)-3-amino-4-ca-rbethoxypyrazole and 225 cc. of hydrazine hydrate is heated for 6 hours at 130 C., then allowed to cool, and the crystals are suctioned oft, treated with ethanol andthe layer insoluble in ethanol is separated. The supernatant alcoholic layer is filtered and adjusted to pH 7.5 with ethanolic hydrochloric acid. The solution is slightly concentrated, whereupon Z-(B-n-propylaminoethyl)-3-aminopyrazole 4 carboxylic acid hydrazide hydrochloride of the formula H-CONHNH2 N J-NHz l CHzCH NHCHzCHzCHa separates out; after having been recrystallized from ethanol it melts at 192-194 C.

Example 14 A solution of 9.3 g. of 2-fi-hydroxyethyl-3-amino-pyrazole-4-carboxylic acid hydrazide and 7.5 g. of S-nitrofurane-Z-aldehyde in 150 cc. of ethanol is heated to the boil for 30 minutes, then allowed to cool, and the precipitate filtered off with suction. The filter residue is recrystallized from much ethyl alcohol. Z-Q-hydroxyethyl- 3-amino-pyrazole-4-carboxylic acid-N-(5-nitro-2 furfurylidene)-hydrazide of the formula is obtained in this manner in the form of yellow crystals of melting point 236237 C. (decomposition).

The 2-,8-hydroxyethyl-3-amino-pyrazole 4 carboxylic acid hydrazide used as starting material is prepared as follows:

19.9 g. 2-j3-hydroxyethyl-3-amino-4-carbethoXy-pyrazole and cc. of hydrazine hydrate are heated together for 6 hours in a bath of 120 C. The reaction mass is then evaporated to dryness under reduced pressure, and the residue crystallized from ethyl alcohol. Z-B-hydroxyethyl-3-amino-pyrazole-4-carboxylic acid hydrazide of the formula is thus obtained in the form of colorless crystals of melting point 236237 C.

What is claimed is:

1. Compounds of the formula;

wherein R is a member selected from the group consisting of the5-R-3-R"-pyrazolyl-(4) radical and such radical substituted at one of the pyrazole ring nitrogen atoms by the radical R'", R being a member selected from the group consisting of hydrogen and lower alkyl, R being a member selected from the group consisting of amino and hydroxy and R' being a member selected from the group consisting of lower alkyl, cyclo-lower alkyl, hydroxy lower alkyl, halogeno-lower alkyl, lower alkoxy-lower alkyl, mercapto-lower alkyl, lower alkylmercapto-lower alkyl, amino-lower alkyl, mono-lower alkyl-amino-lower alkyl, di-lower alkylarnino-lower alkyl, mono-cycloalkylamino-lower alkyl, N-lower alkyl-N-lower cycloalkylamino-lower alkyl, lower alkyleneimino-lower alkyl, mono aza lower alkyleneimino lower alkyl, monooXa-lower alkyleneimino lower alkyl, lower N'-1ower alkyl-mono-aza-lower alkyleneimino-lower alkyl, N'- hydroxy-lower alkyl-mono-aza-lower alkyleneimino-lower alkyl, and phenyl, benzyl and pyridyl and such cyclic radicals substituted by members selected from the group consisting of halogeno, lower alkoxy and nitro.

2. An acid addition salt ofa compound claimed in claim 1.

3. A member selected from the group consisting of a lower alkyland benzyl-ammonium derivative of a compound claimed in claim 1.

4. An N-lower alkanoyl-derivative of a compound claimed in claim 2.

16 5. A compound of the formula:

wherein R is lower alkyleneimino.

7. A compound of the formula:

wherein R is mono-oXa-lower-alkyleneimino.

8. A compound of the formula:

1 lower alkyl 9. A member selected from the group consisting of 2- (fi-diethylamino-ethyD-3 amino-pyrazole 4 carboxylic acid-N'-(S-nitro-Z-furfurylidene) -hydrazide, its alkali metal and its acid addition salts.

10. A member selected from the group consisting of 3- amino-pyrazole-4-carboxylic acid-N-(5-nitro-2-furfurylidene)-hydrazide, its alkali metal and its acid addition salts.

11. A member selected from the group consisting of 2-(/3-piperidino-ethy1)-3 amino-pyrazole 4 carboxylic acid-N'-(5-nitro 2 furfurylidene) hydrazide, its alkali metal and its acid addition salts.

12. A member selected from the group consisting of 2-(fi-morpholino-ethyl)-3-amin0 pyrazole 4 carboxylic acid-N-(5-nitro-2-furfurylidene)-hydrazide, its alkali metal and its acid addition salts.

13. A member selected from the group consisting of 2-is0propyl-3-amino-pyrazole-4-carboxylic acid-N'-(5-nitrO-Z-furfurylidene)-hydra2ide, its alkali metal and its acid addition salts. i

14. A member selected from the group consisting of 2- (ti-is opropylamino-ethyl -3 -amino-pyrazole-4-carboxylic acid-N(S-nitro-furfurylidene)-hydrazide, its alkali metal and its acid addition salts.

15. A member selected from the group consisting of 2-(B-methylamino-ethyl)-3-amino'-pyrazole-4 carboxylic acid-N-(5-nitro 2 furfurylidene) hydrazide, its alkali metal and its acid addition salts.

16. A member selected from the group consisting of 2- fi-dimethylamino-ethyl -3-amino-pyrazole-4-carboxylic acid -N'-(5-nitro-2 furfurylidene)-hydrazide, its alkali metal and its acid addition salts.

17. A member selected from the group consisting of 2- (/3-n-propylamino-ethy1') -3-aminopyrazole 4 carboxylic 1? 18 acid-N'-(5 -nitro-2-furfury1idene) -hydrazide, its alkali met- OTHER REFERENCES 31 and field addmon Salts' Damow et aL, Chemische Berichte, v01. 91, pages 1834-40 (1958). References by the Examiner Mustante et 31., Gazz. Chim. ItaL, v01. 88, pages 930 UNITED STATES PATENTS 5 to 931, 935 and 939 (1958).

2,726,241 12/1955 G t 1 260240 2 57 3/1958 60 247 WALTER MODANCE, Prlmary Exammer.

IRVING MARCUS, NICHOLAS S. RIZZO, Examiners.

FOREIGN PATENTS 594,397 3/1960 Canada. 10 

1. COMPOUNDS OF THE FORMULA: 